Heart failure risk in patients with atrial fibrillation treated with catheter ablation vs antiarrhythmic drugs

Background Atrial fibrillation (AF) increases heart failure (HF) risk. Whereas the risk of HF-related hospitalization and mortality are known in the setting of AF, the impact of AF treatment on HF development is understudied. Objective The purpose of this study was to compare HF incidence among AF patients treated with antiarrhythmic drugs (AADs) vs catheter ablation (CA). Methods AF patients with 1 prior AAD usage were identified in 2014–2022 Optum Clinformatics database. Patients were classified into 2 cohorts: those receiving CA vs those receiving a different AAD prescription. The 2 cohorts were matched on sociodemographic and clinical covariates using propensity score matching technique. Cox regression model was used to compare incident HF risk in the 2 cohorts. Subgroup analyses were performed by race/ethnicity, sex, AF subtype, and CHA2DS2-VASc score. Results After matching, 9246 patients were identified in each cohort (AAD and CA). Patients receiving CA had a 57% lower risk of incident HF than those treated with AADs (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.40–0.46). Subgroup analysis by race/ethnicity depicted similar results, with non-Hispanic White (HR 0.43; 95% CI 0.40–0.46), non-Hispanic Black (HR 0.46; 95% CI 0.35–0.60), Hispanic (HR 0.53; 95% CI 0.40–0.70), and Asian (HR 0.46; 95% CI 0.24–0.92) patients treated with CA (vs AAD) having significantly lower risk of HF, respectively. The effect size of CA remained significant in subgroups defined by sex, AF subtypes, and CHA2DS2-VASc score. Conclusion AF patients receiving CA had ∼57% lower risk of developing HF than those receiving AAD. The lower risk of HF associated with CA vs AAD persisted across different race/ethnicity, sex, AF subtypes, and CHA2DS2-VASc score.


Introduction
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, with the risk of developing AF being up to 25% for both men and women in their lifetime. 1AF affects more than 5.5 million people in the United States (US) and more than 33 million people worldwide. 2Epidemiologic evidence suggests that AF is associated with substantial morbidity and mortality. 3,46][7][8][9] HF can cause debilitating symptoms and sequelae, including shortness of breath, peripheral edema, low cardiac output leading to end-organ damage such as pulmonary hypertension, congestive hepat-opathy, and renal dysfunction, and can lead to mortaility. 10,11iven the increased risk of HF among individuals with AF, the goal of AF treatment should also be predicated on AF management strategies to mitigate this risk.
Catheter ablation (CA) and antiarrhythmic drugs (AADs) are 2 types of treatment modalities that are widely used to treat patients with AF.3][14][15] The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial is a multicenter, prospective, randomized, open-label clinical trial comparing outcomes among AF patients receiving CA vs pharmacologic treatment. 16Although CA (compared to pharmacologic treatment) did not significantly reduce risk of the primary endpoint (death, disabling stroke, serious bleeding, and cardiac arrest) in CABANA, 16 analysis for secondary outcomes suggested that patients receiving CA had a lower risk of death or cardiovascular hospitalization (hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.74-0.93)and AF recurrence (HR 0.52; 95% CI 0.45-0.60)than those receiving pharmacologic treatment (when analyzed by intent-to-treat approach). 17][20] Although previous studies comparing CA with AAD have provided useful information including variation in HFrelated hospitalization and mortality dependent of mode of AF treatment, 21,22 the risk of development of new-onset HF in AF patients receiving CA vs AAD has not been studied.Given the established relationship between AF and HF, we hypothesized that a more effective treatment of AF could potentially mitigate the risk of development of HF.Therefore, the purpose of this study was to compare the incidence of development of new-onset HF among cohorts of patients with AF treated with CA vs AAD.In addition, assessment of HF incidence for CA vs AAD by race/ethnicity and sex was performed.

Data source
In this retrospective cohort study, we used data from the Optum Clinformatics Extended Data Mart-Socio-Economic Status (SES) Database between January 2013 and June 2022.The Optum database is a deidentified administrative claims database containing information from commercially insured individuals or individuals with Medicare Advantage health plans.This database has inpatient, outpatient, and pharmacy claims from approximately 18 million covered lives annually. 23Furthermore, it contains information on SES (eg, education and income) and location for individuals with both medical and pharmacy coverage at the US Census Division level. 24

Study sample
For study purposes, we identified patients (age 18 years) with AF and a history of AAD prescription use (amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotalol, disopyramide, quinidine) for 30 days between January 01, 2014, and June 30, 2022.These patients with AF were then further categorized into 2 study cohorts: those who received CA vs those who were managed with AAD.Patients included in the CA cohort met the following criteria: (1)   (6) had no missing data on study covariates.For patients in the AAD cohort, the following criteria were considered for inclusion: (1) had a subsequent fill for at least 30 days for a different AAD after the initial AAD prescription (with first fill date of the second AAD considered as the index date); (2) had at least 1 medical visit with diagnosis of AF in the preindex AAD period; and (3) had the same condition as criteria 3-6 listed for CA cohort.This yielded a total of 12,983 and 16,346 AF patients for the CA and AAD cohorts, respectively.Detailed information regarding cohort selection is given in Figure 1.
-In this study, the difference in HF risk by treatment modality (CA vs AAD) was consistent across different categories of race/ethnicity, sex, AF subtype, and comorbidity burden.
-Based on the results, our study suggests that use of CA vs AAD for AF treatment could alleviate the risk of HF.
services visit with a diagnosis of HF was treated as outcome of interest for analysis.

Study covariates
Patient sociodemographics including age, sex, race/ethnicity, region, education, and annual household income were assessed.Sex was categorized as male and female.Race/ ethnicity were categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic, Asian, and other.Geographic regions were categorized based on the US Census Bureau regions: Midwest, Northeast, South, and West. 25Education was categorized into high school or lower, without a bachelor degree, bachelor or higher; annual household income was categorized into ,$50K, $50K-$99.9K,and $100K.

Statistical analysis
Propensity score (PS) matching, with 1:1 ratio and greedy match algorithm with 0.10 caliper, was used to match patients in CA and AAD cohorts on all study covariates.After PS matching, we descriptively summarized study characteristics in both CA and AAD cohorts as well.Standardized mean difference (SMD) was used to assess whether distributions of study covariates were well balanced in the 2 cohorts, and |SMD| ,0.25 suggested a balanced distribution. 27fter matching, we summarized the person-year contributed by study participants, number of incident HF in each cohort, and incidence rate of HF during follow-up.We used Kaplan-Meier curve to visualize risk of incident HF and estimate the cumulative incidence of HF in AF patients.A log-rank test was used to assess whether risk differed by treatment modalities.Specifically, in time-to-event analysis, patients entered the risk set at the index and were followed until the diagnosis of incident HF, disenrollment, end of the 3-year follow-up, or uptake of CA (only for AAD cohort), whichever occurred first.A Cox proportional hazards regression model was used to compare risk of incident HF in postmatching cohorts (CA vs AAD), with AAD cohort as the reference group.HR and 95% CI were used as the measure of association.The proportional hazards assumption of the Cox model was examined by visual inspection of log(2log [S]) plot, 28 and there was no violation of this assumption.
To explore whether the difference in risk of HF between treatment modalities (CA vs ADD) varied by race/ethnicity (NHW, NHB, Hispanic, and Asian) and sex (female and male), we conducted subgroup analyses for each of these subpopulations.A previous global survey suggested that HF was more common among persistent AF patients than those with paroxysmal AF 2 ; thus, we performed the analysis in paroxysmal and persistent AF patients, respectively, to explore whether the impact of CA on HF risk varied by AF subtypes.In addition, we conducted a subgroup analysis by CHA 2 DS 2 -VASc score (,4 vs 4) because evidence based on the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network showed that early rhythm control reduced adverse cardiovascular events only for those with CHA 2 DS 2 -VASc score 4. 30 In each set of subgroup analysis, we first applied the same PS matching methods for the subpopulation.We incorporated all covariates used in primary analysis to estimate PS except the factor used for stratification.We then used the Cox proportional hazards regression model to estimate HR and 95% CI for each group.
We conducted 2 sets of sensitivity analysis to explore the stability of the association of CA (compared to AAD) with HF risk.In the first set of sensitivity analysis, patients in the CA cohort were censored when they received a prescription for AAD after the index CA.In the second set of sensitivity analysis, hospitalization with a primary diagnosis of HF was treated as the outcome of interest in time-to-event analysis.
Two-sided P ,.05 was considered significant.Statistical analyses were conducted using R software Version 4.1.2(R Foundation for Statistical Computing, Vienna, Austria) and STATA Version 17 (StataCorp, College Station, TX).

Results
After applying study inclusion and exclusion criteria, 12,983 and 16,346 AF patients were included in the CA and AAD cohorts, respectively (Table 1).In this prematched population, patients in the CA cohort were younger than those in the AAD cohort (64.79 years, SD 9.85 vs 70.07 years, SD 9.92; SMD 0.534).The CA cohort had a lower proportion of female patients than the AAD cohort (37.00% vs 51.03%; SMD 0.285).Significant differences were seen among the CA and AAD prematch cohorts on other study covariates including income, CHA 2 DS 2 -VASc score, insurance plan type, insurance type, utilization of oral anticoagulant, and AF subtype.
After PS matching on all study covariates (as listed in the Study covariates section), a total of 18,492 matched patients were identified, with 9246 patients each in the CA and AAD cohorts, respectively.Postmatching, the CA and AAD cohorts were well balanced on all study covariates, as suggested by SMD values (Table 1).
When examining the Kaplan-Meier curves (Figure 2) along with the log-rank test, results suggested that the risk of incident HF was significantly lower in the CA cohort (log-rank P ,.01).Overall, median follow-up for the sample was 1.14 years, with 3422 incident HF (CA: 1190; AAD: 2232) cases identified during follow-up (Table 2).The CA cohort had a lower cumulative incidence (CA: 18.30%; AAD: 35.09%) and incidence rate (CA: 78.88; AAD: 206.31 per 1000 person-years) of HF than the AAD cohort.Results from Cox regression model (Table 2) depicted a 57% lower risk of incident HF among patients in the CA cohort compared to those in the AAD cohort (HR 0.43; 95% CI 0.40-0.46).Similar results were observed when examined by race/ ethnicity and sex.When examining Kaplan-Meier curves for NHW, NHB, Hispanic, and Asian patients, the risk of incident HF was observed to be significantly lower for the CA cohort compared to the AAD cohort (log-rank test P ,.01 for NHW, NHB, Hispanic, and Asian, respectively;  3).When comparing the risk of incident HF among patients treated with CA vs AAD by sex, similar pattern was observed.Among both males and females, a significantly lower risk of incident HF was observed for those treated with CA vs those treated with AAD (Figure 4).For females, the risk of incident HF was 53% lower among those treated with CA vs those treated with AAD; whereas among males, the risk of incident HF was 59% lower for patients treated with CA vs those treated with AAD (Table 4).
CA was associated with a lower risk of HF (compared to AAD) in both paroxysmal and persistent AF patients (Figure 5), although the effect size seemed to be slightly larger among paroxysmal AF patients (paroxysmal: HR 0.38, 95% CI 0.34-0.42;persistent: HR 0.45, 95% CI 0.40-0.52)(Table 5).The association patterns of treatment modalities with HF risk were similar in subgroups by CHA 2 DS 2 -VASc score (Figure 6 and Table 6).
In the first set of sensitivity analysis, 5950 patients (64.35%) in the CA cohort had AAD prescriptions after the Absolute values of standardized mean difference (SMD) are reported.AAD 5 antiarrhythmic drug; AF 5 atrial fibrillation; CA 5 catheter ablation; EPO 5 exclusive provider organization; HMO 5 health maintenance organization; NHB 5 non-Hispanic Black; NHW 5 non-Hispanic White; POS 5 point of service; PPO 5 preferred provider organization.index, and 653 patients in the CA cohort who developed HF in the primary analysis were censored due to postindex AAD prescription; however, the association remained inverse and significant (HR 0.39; 95% CI 0.35-0.42)(Supplemental Figure 1 and Supplemental Table 1).The effect measure did not change substantially when we used HF hospitalization as the outcome of interest in the analysis (HR 0.45; 95% CI 0.39-0.53)(Supplemental Figure 2 and Supplemental Table 2).

Discussion
With previous data establishing the risks of having concomitant HF and AF within an increasingly aging population, it is imperative to afford proper treatment and management of AF.Using a nationally representative large dataset of commercially insured patients in the US, we followed patients with AF to assess the risk of development of HF dependent on the type of rhythm control strategy provided.We included patients who already had received 1 course of AAD therapy, which is consistent with the current HRS/ EHRA/ECAS/APHRS/SOLAECE (Heart Rhythm Society/ European Heart Rhythm Association/European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm Society/Sociedad Latinoamericana de Estimulación Cardíaca y Electro-fisiología [Latin American Society of Cardiac Stimulation and Electrophysiology]) guidelines that favor ablation when refractory AF or intolerance of antiarrhythmic medications are identified among patients with AF. 28 Our cohort shows a significant risk of developing new-onset HF in patients with AF, which is consistent with previous global evidence suggesting that HF rates vary between 33% and 56% by AF subtypes. 29,31To the best of our knowledge, this is the first such study to examine and compare the incidence of HF among patients with AF treated with CA vs AAD.In our study, patients with AF receiving CA were observed to have a 57% lower risk of developing incident HF compared to those treated with AAD.Given the novelty of our analysis and the lack of comparable evidence, a direct comparison of our results to previous studies is not feasible; however, a few studies have examined HF-related hospitalizations among patients with AF treated with CA vs AAD.Results from prespecified as-treated analysis from CABANA suggested a 41% reduction in the composite of death or HF hospitalization (HR 0.59; 95% CI 0.41-0.87)for the CA arm vs the AAD arm. 32In their analysis of a large retrospective dataset, Jarman et al 22 observed a 38% lower risk of HF-related hospitalization over a 3-year period for patients with AF treated with CA vs AAD (HR 0.62; P 5 .0318).However, another observational study examining 3-year  risk of inpatient admission with HF as the primary diagnosis did not observe any significant difference among patients with AF treated with CA vs AAD (HR [CA vs AAD] 5 0.69; 95% CI 0.42-1.15). 21Our results, although not directly comparable, suggest that in addition to the potential to reduce the burden of HF, CA treatment could alter the disease course to reduce the risk of incident HF in the first place among AF patients.
The lower risk of incident HF among patients with AF treated with CA vs AAD was observed to be consistent across difference race/ethnicity categories.The effect size of HR in each race/ethnicity group suggests that     the potential protective effects of CA in comparison to AAD on incident HF are consistent across NHW, NHB, Hispanic, and Asian patients with AF.The results were also consistent across sex categories, with AF patients treated with CA having significantly lower risk of incident HF than those treated with AAD.
Some factors can explain why AF patients in our ablation cohort had a lower HF risk than counterparts receiving AAD.Among AF patients, the increased heart rate, atrial stretch, and irregularity of the ventricular cycle can contribute to reduced cardiac output, remodeling, and cardiac dysfunction resulting in HF. 33 Several metaanalyses [34][35][36] of randomized controlled trials compared outcomes of AF patients receiving CA vs AADs, and the synthesized results suggested that CA was more effective in maintaining sinus rhythm in comparison to antiarrhythmic therapy regardless of medication used.Therefore, by providing improvement of arrhythmia burden and maintaining normal rhythm, CA has better potential to reduce the likelihood of downstream adverse events of AF such as HF.

Study limitations
This is a retrospective analysis of AF patients who had received either CA or AAD as a second-line therapy.The magnitude of risk of developing HF may not be equivalent to patients who have not received previous antiarrhythmic therapy.This study also excluded patients with surgical or catheter ablation of AF as well as valvular procedures or cardiac implantable device implantation during the 12 months before the index because these procedures could influence incidence of HF.Although we used PS matching to balance the study cohorts on covariates of interest, unmeasured confounding such as severity of AF and left ventricular ejection fraction could have influenced study results.Additionally, misclassification could have occurred during the coding process for the claims and impacted our results.Our study may have misclassification of new-onset HF because the HF diagnosed in outpatient settings could be underreported, and these HF patients might have pre-existing symptoms that were not documented and therefore not new onset.The Optum SES database does not contain information on death, which is an important competing risk of HF during follow-up, making the estimated cumulative incidence biased upward. 37The database does not have a measure to reflect postindex AF burden, making us unable to explore whether the lower HF risk is a downstream event of the reduced AF burden.Lastly, the Optum database includes patients with commercial insurance in the US, and our results may not represent uninsured populations.

Conclusion
In this examination of a large real-world dataset, AF patients with no history of HF who underwent CA were observed to have a significantly lower risk of incident HF compared to those who received AAD.The mitigation of HF risk associated with CA treatment was consistent across different race/ ethnicity and sex categories.These results provide decisionmaking evidence for both clinicians and patients regarding potential subsequent sequelae of AF therapy.A prospective study with measures of AF severity and heart function (eg, left ventricular ejection fraction) will be needed in future to further compare the risk of HF in AF patients treated with CA vs AAD.
26 Patient clinical characteristics including Elixhauser Comorbidity Index and CHA 2 DS 2 -VASc were assessed.Insurance type (Medicare, commercial insurance, both) and type of insurance plan (health maintenance organization [HMO] or exclusive provider organization [EPO], preferred provider organization [PPO], point of service [POS] or indemnity, other) were assessed.Utilization of prescription drugs including beta-blockers, calcium channel blockers, and oral anticoagulants were also defined.

Figure 2
Figure 2 Kaplan-Meier curve of incidence of heart failure (HF) by treatment modality.AAD 5 antiarrhythmic drug; CA 5 catheter ablation.

Figure 3
Figure 3 Kaplan-Meier curves of incidence of heart failure (HF) by treatment modality in different race/ethnicity groups: non-Hispanic White (A), non-Hispanic Black (B), Hispanic (C), and Asian (D).AAD 5 antiarrhythmic drug; CA 5 catheter ablation.

Figure 4
Figure 4 Kaplan-Meier curves of incidence of heart failure (HF) by treatment modality in different sex groups: female (A) and male (B).AAD 5 antiarrhythmic drug; CA 5 catheter ablation.

Figure 5
Figure 5 Kaplan-Meier curve of incidence of heart failure (HF) by treatment modality in different atrial fibrillation subtypes: paroxysmal (A) and persistent (B).AAD 5 antiarrhythmic drug; CA 5 catheter ablation.
.govinfo.gov/content/pkg/CFR-2011-title45-vol1/pdf/CFR-2011-title45-vol1.pdf).As Optum data do not contain direct identifiers of individuals, employers, households, or providers, Institutional Review Board approval was not required.The research reported in this article adhered to Helsinki Declaration guidelines.
This analysis of the Optum Clinformatics database was conducted under an exemption from Institutional Review Board oversight for US-based studies using deidentified health care records, as dictated by Title 45 Code of Federal Regulations (45 CFR 46.101(b)(4)) (https:// www

Table 1
Characteristics of the study population

Table 3
Risk of HF by treatment modality in subgroups defined by race/ethnicity NHB 5 non-Hispanic Black; NHW 5 non-Hispanic White; other abbreviations as in Table2.

Table 4
Risk of HF by treatment modality in female and male patients Abbreviations as in Table2.

Table 5
Risk of HF by treatment modality in paroxysmal and persistent atrial fibrillation